Aromatase inhibition to enhance assisted reproduction

ABSTRACT

The use of at least one aromatase inhibitor in the production of a medicament for improving the implantation and pregnancy rates for a female undergoing assisted reproduction treatment, which comprises one or more daily doses of an aromatase inhibitor (AI) for administration during assisted reproduction cycles or ovarian stimulation cycles, wherein the doses of AI are selected from amounts effective to reduce serum estradiol levels. Also disclosed are related pharmaceutical preparations and packages.

FIELD OF THE INVENTION

This invention relates to a method for treating females undergoingassisted reproduction treatment and ovulation induction which involvesadministration of an aromatase inhibitor (AI). Also disclosed arepreparations and related uses. There is also described a method forincreasing production of follicles in a female for the purpose ofharvesting immature eggs for oocyte maturation in vitro which alsoinvolves the administration of AI.

BACKGROUND OF THE INVENTION

In most assisted reproduction programs, gonadotropins are used alone orin combination to stimulate the growth and maturation of multipleoocytes. This is essential because of the need to recruit a greaternumber of follicles, which improves the chance of fertilization and anincreased number of embryos for transfer to give acceptable successrates. Recent advances in the understanding of ovarian stimulation, thetechniques of oocyte retrieval, the handling of gametes, the methods ofassisted fertilization and improved conditions of culture media havesteadily increased the fertilization rate. Oocyte fertilization rates of60-70% can now be expected when conventional insemination orintracytoplasmic sperm injection (ICSI) are carried out. However, therehas not been a corresponding increase in implantation rates, which haveremained steady at 10-15% per embryo¹.

It is believed that the high, supraphysiologic levels of estrogen,attained during ovarian stimulation, may result in an adverse effect ofovarian stimulation on the outcome of infertility treatment. Significantdecreases in pregnancy and implantation rates have been observed whenestradiol concentrations were >10,000 pmol/L compared with patientshaving lower estradiol concentrations². High serum estradiolconcentrations on the day of HCG injection in IVF patients, regardlessof the number of oocytes retrieved, were found to be detrimental touterine receptivity³. Recently, it has been shown that a significantreduction in implantation and pregnancy rates occurred in almost allwomen with a serum estradiol concentration greater than 20,000 pmol/L⁴.

Different mechanisms have been postulated to explain the adverse effectof the supraphysiologic levels of estrogen including deleterious effectson the endometrium and the embryo, although the exact mechanisms havenot yet been determined.

Effect of Supraphysiologic Levels of Estrogen on Implantation:

There is controversy regarding the effect of ovarian hyperstimulation onendometrial development. Most investigators have reported adverseeffects of high estrogen levels on endometrial development but there wasno consensus on the actual mechanism of this effect. Endometrialbiopsies for dating have shown both endometrial advancement andendometrial retardation in relation to high serum estradiolconcentrations. However, all studies confirm direct effects onendometrial development that may jeopardize the chance of implantationdue to the lack of synchronization between the endometrium and earlyembryo development. Such synchronization is crucial for successfulimplantation (window of implantation).

Various studies have shown a high incidence of endometrial glandularadvancement⁵ and retardation⁶ using morphological andimmunohistochemical criteria⁷. One study of natural versus ovarianstimulation cycles, demonstrated an advanced development of theultrastructure of endometrial surface epithelium in the stimulationcycles⁸. However, another investigation demonstrated that ovulationinduction was not associated with abnormal endometrial development⁹.

More recently, the effect of excessively high estradiol concentrations(>20,000 pmol/L) were found to be associated with a deficient secretorytransformation of the endometrium and a suboptimal endometrialenvironment for implantation. This finding supports clinicalobservations of significantly lower pregnancy rates in IVF cycles inwomen with estradiol concentrations ≧20,000 pmol/l. In these patients,there was a marked stromal oedema associated with a significantlygreater number of vessels, and advanced stromal maturation possiblyrepresenting a direct effect of high estradiol levels on theendometrium¹⁰. In another study, an asynchronous development ofendometrial glands and stromal was found in women undergoing IVF¹¹.

Most recently, a detrimental effect of high estrogen concentrations hasbeen demonstrated on the embryo itself. Decreased blastocyst formationand reduce embryo adhesion to an endometrial cell layer was observed inthe presence of elevated estrogen concentrations¹².

It appears that excessive estradiol production during controlled ovarianstimulation leads to insufficient secretory transformation of theendometrium and a discordant glandular and stromal development at a timethat coincides with the period of maximum uterine receptivity. Inaddition, there are possible adverse effects directly oh the embryo thatcould reduce the chance for implantation. This may explain the findingsof decreased implantation and pregnancy rates in IVF when serumestradiol concentrations are exceptionally high.

Measures to Improve Pregnancy Outcome by Reducing E2 Levels:

Different approaches have been suggested to improve the treatmentoutcome during assisted reproduction by reducing the intensity ofovarian stimulation to reduce the high estrogen levels. These approachesincluded minimal stimulation IVF cycles and natural cycle IVF which havebeen reported to be effective methods of treatment for ovulatory womenundergoing assisted conception¹³. Other measures to lower estrogenlevels include decreasing the FSH dose (step down protocol). With theuse of a step-down FSH regimen in high responders, uterine receptivitymay be improved secondary to lowering E2 levels during thepreimplantation period¹⁴. Coasting or withholding FSH injections for aperiod of time prior to administration of hCG has been suggested inpatients at substantial risk for the development of severe ovarianhyperstimulation syndrome (OHSS) and is associated with loweredestradiol levels¹⁵. However, all these measures are associated with themajor drawback of decreasing the number of oocytes retrieved and embryosproduced.

Aromatase Inhibition

As discussed above, the undesirable effects of ovarian stimulation onthe outcome of infertility treatment may be due to the supraphysiologiclevels of estrogen. Lowering estrogen levels may be associated withimproved outcome by improving the implantation and pregnancy rates inaddition to lowering risk of severe ovarian hyperstimulation syndrome.Reducing estrogen synthesis by aromatase inhibition during assistedreproductive technologies could be a way to ameliorate the deleteriouseffects of the supraphysiologic levels of estrogen during ovarianstimulation.

Until recently there was no effective aromatase inhibitor that could beused clinically to reduce estrogen levels during ovarian stimulation.This is because the available aromatase inhibitors (e.g.aminoglutethemide) lacked specificity to inhibit the aromatase enzymewithout inhibiting other steroidogensis enzymes. The other aromataseinhibitors (steroidal androstenedione analogues) were irreversible intheir effect on the aromatase enzyme and needed to be parentallyadministered. Most important, these old aromatase inhibitors were notpotent enough to inhibit the aromatase and lower estrogen levels inwomen of the reproductive age group. A new group of non-steroidalaromatase inhibitors (letrozole, anastrazole and vorazole) is verypotent and specific, reversibly inhibiting aromatase when orallyadministered with very high safety profile. Moreover, they have arelatively short half-life.

In Vitro Fertilization and In Vitro Maturation

It is useful to review in vitro fertilization and in vitro maturationfor purposes of understanding the present invention. In vitrofertilization (IVF) in conventional use involves daily injections offertility drugs, usually gonadotropins. Oocytes grow inside folliclesand mature in the body. The mature oocytes are retrieved and fertilizedby adding sperm in vitro in the laboratory.

In vitro maturation (IVM) does not necessarily involve the use offertility drugs or may involve decreased doses of gonadotrophins whencompared with IVF or OI. In the procedure, which is well documented inthe literature, immature oocytes are retrieved from the female ovary atabout day 7 for natural or artificial exogenous (gonadotrophins used)cycle and matured in vitro in the laboratory. Mature oocytes are thenfertilized in the laboratory by intra-cytoplasmic sperm injection(ICSI). This procedure was developed for infertile women with polycysticovary syndrome (PCOS). The advantages over in vitro fertilization (IVF)are reduced exposure to fertility drugs, reduced requirements forpatient monitoring and because of the reduced exposure to fertilitydrugs, drug side effects are substantially eliminated, especially thoseassociated with ovarian hyperstimulation syndrome (OHSS).

The procedure for IVM comprises the following steps:

-   -   Menstrual bleeding is induced by progestin.    -   Ultrasound (U/S) scan is performed on day 6-9 of the cycle.    -   Blood is drawn for maternal serum at time of U/S.    -   PCOS pattern of follicles without a dominant follicle (1.5 cm or        greater) is seen at this time.    -   Human chorionic gonadotropin (hCG) 10,000 IU is given to the        patient using vaginal ultrasound-guided needle aspiration and        local anesthesia.    -   Egg retrieval 36 hours later and egg collection takes 15 to 30        minutes.    -   The harvested immature oocytes are cultured in maturation medium        for 24 hours.    -   A fresh sperm sample from the female's partner is prepared for        insemination.    -   The mature oocytes are then fertilized by ICSI.    -   Fertilization is checked at 16 hours after ICSI.    -   The fertilized oocytes are cultured for another 2 days.    -   Natural progesterone (Prometrium) is started vaginally (200 mg        twice daily) on the day of oocyte insemination.    -   Two or three embryos (or one to two blastocysts) are transferred        into the uterus.    -   Embryo transfer takes a few minutes and is painless.

SUMMARY OF THE INVENTION

Although aromatase inhibitors have not been used in women of thereproductive age group, we have discovered the effectiveness of thesedrugs, to decrease estrogen levels in women of the reproductive agegroup. Moreover, we found that estrogen levels following induction oraugmentation of ovulation with aromatase inhibitors were significantlylower (especially serum E2 concentration/mature follicle) when comparedwith conventional stimulation protocols.

A reduction in E2 levels is beneficial in improving pregnancy outcome ofassisted reproduction treatment. The use of aromatase inhibition reducesthe supraphysiologic levels of estrogen during assisted reproductivetechnology cycles to improve the implantation and pregnancy rates insuch cycles. As a result, fewer embryos need to be transferred toachieve a pregnancy thereby reducing the risk of multiple pregnancies. Areduction in E2 levels may also be beneficial in reducing the risk ofovarian hyperstimulation syndrome (OHSS).

Assisted Reproductive Technologies (ART)

Assisted reproductive technologies (ART) includes, for example, thefollowing techniques:

In vitro fertilization (IVF), in which oocytes are aspirated frompre-ovulatory follicles, combined with sperm in vitro and viable embryosare selected and placed in the uterus.

Gamete Intrafallopian Transfer Procedure (GIFT), in which oocytes andsperm are combined in a catheter, and placed in the fallopian tube, sothat conception occurs in the fallopian tube.

Zygote Intrafallopian Transfer Procedure (ZIFT), in which the collectedoocytes are combined with sperm, and fertilized embryos are transferredto the fallopian tube.

Intracytoplasmic Sperm Injection (ICSI), in which each oocyte isdirectly injected With a single sperm via a microscopic needle, andviable embryos are selected for placement in the uterus or the fallopiantube.

Intrauterine insemination (IUI). Intrauterine insemination (IUI) is afertility procedure in which motile sperm are washed, concentrated, andinjected directly into a woman's uterus.

Therapeutic Donor insemination (TDI) involves the use of timedinsemination of sperm from a donor rather than from the husband.

Controlled ovarian Hyperstimulation (COH) for timed intercourse, for IUIor for other ART procedures such as IVF encompasses the concept ofdeliberate and regulated induction of superovulation, but also refers toproduction of a hormonal response intended to lead to the production ofmultiple eggs in the woman's ovaries and to favor implantation of theembryo into the endometrium.

Thus, the present invention provides a method for improving theimplantation and pregnancy rates for females undergoing assistedreproduction treatment (e.g. IVF, GIFT, ZIFT, ICSI, IUI, TDI and COH) orovarian stimulation cycles for ovulation induction, which comprisesadministering to such females one or more daily doses of an aromataseinhibitor (AI) during assisted reproduction cycles or ovarianstimulation cycles, wherein the doses of AI are selected from amountseffective to reduce serum estradiol levels.

The invention also provides a method of increasing the production offollicles below the size of dominant follicles for the purpose ofharvesting immature eggs for oocyte maturation in vitro byadministration of one or more daily doses of at least one aromataseinhibitor to a female early in one or more menstrual cycles. Dominantfollicles are generally more than 1.0 cm in diameter. Preferably thistreatment eliminates the need for FSH treatment altogether and preventsthe occurrence of ovarian hyperstimulation (OHSS). The AI is preferablyadministered as early as possible in the menstrual cycle so as to avoidhaving a negative impact on the developing embryo.

All patients undergoing COH with FSH suffer from high estrogen levelsassociated with higher follicle numbers, whether undergoing ovulationinduction regimen or regimens for ART.

Preferably, from 1 to 10 daily doses of the aromatase inhibitor areadministered. Most preferably, a total of 5 or fewer daily doses of thearomatase inhibitor are administered or a single dose of the AI isadministered.

In another aspect the invention provides a method for improving theimplantation and pregnancy rates for females undergoing assistedreproduction treatment which comprises administering a combination ofone or more daily doses of at least one aromatase inhibitor (AI) with aplurality of daily doses of follicle stimulating hormone (FSH).

In some commercial forms of FSH, lutenizing hormone (LH) may also bepresent, and hence, the invention also encompasses daily doses of FSHand LH in place of daily doses of FSH alone. A particular example ofsuch a mixed preparation is human menopausal gonadotrophin (hMG), whichis a 1:1 mixture (I.U./I.U.) of FSH and LH.

Another aspect of the invention provides a pharmaceutical preparationfor improving the implantation and pregnancy rates for femalesundergoing assisted reproduction treatment comprising one or more dailydoses of a composition comprising an effective amount for improving theimplantation and pregnancy rates for females of an aromatase inhibitortogether with a pharmaceutically acceptable carrier.

The invention also provides for a two component pharmaceuticalpreparation for improving the implantation and pregnancy rates forfemales comprising one or more daily doses of an aromatase inhibitortogether with a pharmaceutically acceptable carrier in combination witha plurality of daily doses of follicle stimulating hormone together witha pharmaceutically acceptable carrier.

Another aspect of the invention comprises a pharmaceutical preparationfor increasing the production of follicles below the size of dominantfollicles for the purpose of harvesting immature eggs for oocytematuration in vitro which comprises one or more daily doses of at leastone aromatase inhibitor together with a pharmaceutically acceptablecarrier.

The invention also provides the use of one or more daily doses of anaromatase inhibitor either alone or in combination with a plurality ofdaily doses of follicle stimulating hormone for improving implantationand pregnancy rates for females, in ovarian stimulation for ovulationinduction, in ART, and in a natural cycle.

The invention also provides for the use of one or more daily doses of atleast one aromatase inhibitor in amounts effective to reduce serumestradiol levels for increasing the production of follicles below thesize of dominant follicles for the purpose of harvesting immature eggsfor oocyte maturation in vitro.

Another part of the invention comprises the use of one or more dailydoses of an aromatase inhibitor in the preparation of a medicament forimproving the implantation and pregnancy rates for females.

The use of an aromatase inhibitor during ovulation induction cycles andcycles for ART decreases the dose of FSH required.

In ART cycles in which the development of multiple follicles isstimulated with FSH or hMG (controlled ovarian hyperstimulation, COH),the high number of follicles causes estrogen levels to increasesubstantially. The increased estrogen levels may trigger the release ofan LH surge from the pituitary. The sudden increase in LH levels maycause some developing follicles to luteinise and thus not yield oocytes.Other follicles may release their oocytes into the fallopian tubes,which is undesirable for ART cycles. (In ART cycles the oocytes arecollected prior to release, by aspiration from the pre-ovulatoryfollicle.) In order to prevent such an LH surge, a GnRH agonist or GnRHantagonist is given to induce a state called down-regulation. Theagonist or antagonist suppresses pituitary gonadotrophins, thuspreventing an endogenous LH surge. This allows controlled timing foradministering the hCG bolus and oocyte collection.

The inventors have found that estrogen levels can be decreased duringstimulation with FSH or a mixture of FSH and LH, by administration of anaromatase inhibitor. Because of the decreased estrogen levels, an LHsurge can be prevented. When aromatase activity is suppressed, estrogenlevels remain within a normal range for a natural cycle in a healthypatient, or even below this level, at the level of a post-menopausalwoman, or even below the level detectable with common immunoassays.Because of the lower estrogen levels, the pituitary will not respondwith an LH surge. The use of an aromatase inhibitor can effectivelyreplace the use of a GnRH agonist or antagonist in some patients.

While one aromatase inhibitor is preferred for use in the presentinvention, combinations of aromatase inhibitors may be used especiallythose of aromatase inhibitors having different half-lives. The aromataseinhibitor is preferably selected from aromatase inhibitors having ahalf-life of about 8 hours to about 4 days, more preferably fromaromatase inhibitors having a half-life of about 2 days. Most beneficialare those aromatase inhibitors selected from non-steroidal andreversible aromatase inhibitors. More detail on the types of aromataseinhibitors that may be used in the methods, uses, preparations andpackages of the present invention appears subsequently herein.

The aromatase inhibitors that have been found to be most useful of thecommercially available forms are those in oral form. This form offersclear advantages over other forms, including convenience and patientcompliance. Preferred aromatase inhibitors of those that arecommercially available include anastrozole, letrozole, vorozole andexemestane. Exemestane (Aromasin™) is an example of a steroidalaromatase inhibitor that may be used in the present invention.

The daily doses required for the present invention depend on the type ofaromatase inhibitor that is used. Some inhibitors are more active thanothers and hence lower amounts of such inhibitors could be used.

Typically, the amount of aromatase inhibitor for the improvedimplantation and pregnancy rates may be selected from amounts that lowerestrogen levels to about normal physiological levels in a female suchthat serum estradiol concentration is less than at or about 10,000pmol/L, preferably from at or about 300 to at or about 5000 pmol/L. in afemale. In the case of increasing the production of follicles below thesize of dominant follicles, the AI may be administered in amounts thatlower estrogen levels to post menopausal levels in a female. For examplethe amount of aromatase inhibitor may be selected from amounts thatlower the level of estrogen to at or about 100 pmol/L or less asmeasured by standard immunoassay techniques. These techniques are wellknown to those skilled in the art.

Examples of preferred suitable dosages are as follows. When thearomatase inhibitor is selected from anastrozole, letrozole andvorozole, the daily dose administered may be an amount in the range fromat or about 1 mg to at or about 10 mg. When the aromatase inhibitor isexemestane, the amount administered in a daily dose may range from at orabout 10 mg to at or about 200 mg. When the aromatase inhibitor isletrozole, it is preferably administered in a daily dose of from at orabout 2.5 mg to at or about 10.0 mg. When the aromatase inhibitor isanastrozole, preferably, it is administered in a daily dose of from ator about 1 mg to at or about 4 mg. When the aromatase inhibitor isvorozole, the preferred daily dose is from at or about 2 to at or about8 mg. Exemestane is preferably administered in a daily dose of at orabout 25 to at or about 50 mg. Preferred are 1 to 10 daily doses of thearomatase inhibitor with administration starting on any of days 1 to 5of the menstrual cycle. Most preferably the daily doses of the aromataseinhibitor comprise five daily doses. Most preferably the daily doses areadministered sequentially.

In another preferred form of the invention a single dose of AI isadministered in place of the multiple daily doses described above. Thearomatase inhibitor is preferably administered in a single dose selectedfrom amounts in the range of from at or about 5 mg to at or about 500 mg(e.g., at or about 10 mg, 20 mg, 25 mg or 30 mg to at or about 500 mg)and when the FSH is used, daily doses of follicle stimulating hormonerange from at or about 25 to at or about 600 units (e.g., at or about 50to at or about 225 units, e.g., to at or about 150 units) or anequivalent dosage in another form of administration.

The FSH used may be any of the commercially available products,including urinary and recombinant FSH. FSH may also be used in a form,which includes LH (Luteinizing Hormone).

The dosages for FSH may range from at or about 25 to at or about 600units daily or its equivalent in other delivery forms with the period ofadministration being from about 1 to about 15 days. The FSH may beadministered simultaneously, separately, sequentially, consecutively,with or without a gap or with some dosage overlap, with the AI.

Other types of ovulatory infertility which may be treated in accordancewith the present invention may include endometriosis, cervical mucusabnormalities, older patients, (e.g. older than at or about 35,preferably younger than at or about 50, more preferably younger than ator about 45, most preferably at or about 38 to at or about 42) increasedbaseline FSH concentration, elevated FSH concentration, and low malesperm count (male factor infertility) requiring IUI (IntrauterineInsemination) or TDI (therapeutic donor insemination) in whichaugmenting ovulation in the female partner is indicated.

While female here is preferably a human being, the treatments may beapplied to other species as appropriate.

Aromatase Inhibitor

By “aromatase inhibitors” there are to be understood substances thatinhibit the enzyme aromatase (estrogen synthetase), which is responsiblefor converting androgens to estrogens.

Aromatase inhibitors may have a non-steroidal or a steroidal chemicalstructure. According to the present invention, both non-steroidalaromatase inhibitors and steroidal aromatase inhibitors can be used.

By aromatase inhibitors there are to be understood especially thosesubstances that in a determination of the in vitro inhibition ofaromatase activity exhibit IC₅₀ values of 10⁻⁵ M or lower; especially10⁻⁶ M or lower, preferably 10⁻⁷ M or lower and most especially 10⁻⁸ Mor lower.

The in vitro inhibition of aromatase activity can be demonstrated, forexample, using the methods described in J. Biol. Chem. 249, 5364 (1974)or in J. Enzyme Inhib. 4, 169 (1990). In addition, IC₅₀ values foraromatase inhibition can be obtained, for example, in vitro by a directproduct isolation method relating to inhibition of the conversion of4-¹⁴ C-androstenedione to 4-¹⁴ C-oestrone in human placental microsomes.

By aromatase inhibitors there are to be understood most especiallysubstances for which the minimum effective dose in the case of in vivoaromatase inhibition is 10 mg/kg or less, especially 1 mg/kg or less,preferably 0.1 mg/kg or less and most especially 0.01 mg/kg or less.

In vivo aromatase inhibition can be determined, for example, by thefollowing method [see J. Enzyme Inhib. 4, 179 (1990)]: androstenedione(30 mg/kg subcutaneously) is administered on its own or together with anaromatase inhibitor (orally or subcutaneously) to sexually immaturefemale rats for a period of 4 days. After the fourth administration, therats are sacrificed and the uteri are isolated and weighed. Thearomatase inhibition is determined by the extent to which thehypertrophy of the uterus induced by the administration ofandrostenedione alone is suppressed or reduced by the simultaneousadministration of the aromatase inhibitor.

The following groups of compounds are listed as examples of aromataseinhibitors. Each individual group forms a group of aromatase inhibitorsthat can be used successfully in accordance with the present invention:

(a) The compounds of formulae I and I* as defined in EP-A-165 904. Theseare especially the compounds of formula I

wherein R₁ is hydrogen, lower alkyl; lower alkyl substituted by hydroxy,lower alkoxy, lower alkanoyloxy, lower alkanoyl, amino, loweralkylamino, di-lower alkylamino, halogen, sulfo, carboxy, loweralkoxycarbonyl, carbamoyl or by cyano; nitro, halogen, hydroxy, loweralkoxy, lower alkanoyloxy, phenylsulfonyloxy, lower alkylsulfonyloxy,mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl,lower alkanoylthio, amino, lower alkylamino, di-lower alkylamino, loweralkyleneamino, N-morpholino, N-thiomorpholino, N-piperazino piperazinothat is unsubstituted or lower alkyl-substituted in the 4-position,tri-lower alkylammonio, sulfo, lower alkoxysulfonyl, sulfamoyl, loweralkylsulfamoyl, di-lower alkylsulfamoyl, formyl; iminomethyl that isunsubstituted or substituted at the nitrogen atom by hydroxy, loweralkoxy, lower alkanoyloxy, lower alkyl, phenyl or by amino; C₂-C₇alkanoyl, benzoyl, carboxy, lower alkoxycarbonyl, carbamoyl, loweralkylcarbamoyl, di-lower alkylcarbamoyl, cyano, 5-tetrazolyl,unsubstituted or lower alkyl-substituted 4,5-dihydro-2-oxazolyl orhydroxycarbamoyl; and R₂ is hydrogen, lower alkyl, phenyl-lower alkyl,carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, halogen, hydroxy,lower alkoxy, lower alkanoyloxy, mercapto, lower alkylthio, phenyl-loweralkylthio, phenylthio, lower alkanoylthio, carboxy, lower alkoxycarbonylor lower alkanoyl; the 7,8-dihydro derivatives thereof; and thecompounds of formula I*

wherein n is 0, 1, 2, 3 or 4; and R₁ and R₂ are as defined above forformula I; it being possible for the phenyl ring in the radicalsphenylsulfonyloxy, phenyliminomethyl, benzoyl, phenyl-lower alkyl,phenyl-lower alkylthio and phenylthio to be unsubstituted or substitutedby lower alkyl, lower alkoxy or by halogen; it being possible in acompound of formula I* for the two substituents C₆ H₄—R₁ and R₂ to belinked to each of the saturated carbon atoms of the saturated ring,either both to the same carbon atom or both to different carbon atoms,and pharmaceutically acceptable salts thereof.

Individual compounds that may be given special mention here are:

-   (1) 5-(p-cyanophenyl)imidazo[1,5-a]pyridine,-   (2) 5-(p-ethoxycarbonylphenyl)imidazo[1,5-a]pyridine,-   (3) 5-(p-carboxyphenyl)imidazol[5-a]pyridine,-   (4) 5-(p-tert-butylaminocarbonylphenyl)imidazo[1,5-a]pyridine,-   (5)    5-(p-ethoxycarbonylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (6) 5-(p-carboxyphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (7) 5-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (8) 5-(p-tolyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (9) 5-(p-hydroxymethylphenyl)imidazo[1,5-a]pyridine,-   (10) 5-(p-cyanophenyl)-7,8-dihydroimidazo[1,5-a]pyridine,-   (11) 5-(p-bromophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (12)    5-(p-hydroxymethylphenyl)5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (13) 5-(p-formylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (14)    5-(p-cyanophenyl)-5-methylthio-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (15)    5-(p-cyanophenyl)-5-ethoxycarbonyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (16) 5-(p-aminophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (17) 5-(p-formylphenyl)imidazo[1,5-a]pyridine,-   (18) 5-(p-carbamoylphenyl)imidazo[1,5-a]pyridine,-   (19)    5H-5-(4-tert-butylaminocarbonylphenyl)-6,7-dihydropyrrolo[1,2-c]imidazole,-   (20) 5H-5-(4-cyanophenyl)-6,7-dihydropyrrolo[1,2]imidazole,-   (21) 5H-5-(4-cyanophenyl)-6,7,8,9-tetrahydroimidazo[1,5-a]azepine,-   (22)    5-(4-cyanophenyl)-6-ethoxycarbonylmethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (23)    5-(4-cyanophenyl)-6-carboxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine-   (24)    5-benzyl-5-(4-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (25) 7-(p-cyanophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (26) 7-(p-carbamoylphenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (27) 5-(p-cyanophenyl)5,6,7,8-tetrahydroimidazo[1,5-a]pyridine    (=Fadrozol).    (b) The compounds of formula I as defined in EP-A 236 940. These are    especially the compounds of formula I

wherein R and R₀, independently of one another, are each hydrogen orlower alkyl, or R and R₀ at adjacent carbon atoms, together with thebenzene ting to which they are bonded, form a naphthalene ortetrahydronaphthalene ring; wherein R₁ is hydrogen, lower alkyl, aryl,aryl-lower alkyl or lower alkenyl; R₂ is hydrogen, lower alkyl, aryl,aryl-lower alkyl, (lower alkyl, aryl or aryl-lower alkyl)-thio or loweralkenyl, or wherein R₁ and R₂ together are lower alkylidene or C₄-C₆alkylene; wherein W is 1-imidazolyl, 1-(1,2,4 or 1,3,4)-triazolyl,3-pyridyl or one of the mentioned heterocyclic radicals substituted bylower alkyl; and aryl within the context of the above definitions hasthe following meanings: phenyl that is unsubstituted or substituted byone or two substituents from the group lower alkyl, lower alkoxy,hydroxy, lower alkanoyloxy, nitro, amino, halogen, trifluoromethyl,cyano, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl, lower alkanoyl, benzoyl, loweralkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl and N,N-di-loweralkylsulfamoyl; also thienyl, indolyl, pyridyl or furyl, or one of thefour last-mentioned heterocyclic radicals monosubstituted by loweralkyl, lower alkoxy, cyano or by halogen; and pharmaceuticallyacceptable salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 4-[alpha-(4-cyanophenyl)-1-imidazolylmethyl]-benzonitrile,-   (2) 4-[alpha-(3-pyridyl)-1-imidazolylmethyl]-benzonitrile,-   (3) 4-[alpha-(4-cyanobenzyl)-1-imidazolylmethyl]-benzonitrile,-   (4) 1-(4-cyanophenyl)-1-(1-imidazolyl)-ethylene,-   (5)    4-[alpha-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-benzonitrile,-   (6) 4-[alpha-(4-cyanophenyl)-3-pyridylmethyl]-benzonitrile.    (c) The compounds of formula I as defined in EP-A408 509. These are    especially the compounds of formula I

wherein Tetr is 1- or 2-tetrazolyl that is unsubstituted or substitutedin the 5-position by lower alkyl, phenyl-lower alkyl or by loweralkanoyl; R and R₂, independently of one another, are each hydrogen;lower alkyl that is unsubstituted or substituted by hydroxy, loweralkoxy, halogen, carboxy, lower alkoxycarbonyl, (amino, lower alkylaminoor di-lower alkylamino)-carbonyl or by cyano; lower alkenyl, aryl,heteroaryl, aryl-lower alkyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl-loweralkyl, lower alkylthio, arylthio or aryl-lower alkylthio; or R₁ and R₂together are straight-chained C₄-C₆ alkylene that is unsubstituted orsubstituted by lower alkyl, or are a group—(CH₂)_(m)-1,2-phenylene-(CH₂)_(n)— wherein m and n, independently ofone another, are each 1 or 2 and 1,2-phenylene is unsubstituted orsubstituted in the same way as phenyl in the definition of aryl below,or are lower alkylidene that is unsubstituted or mono- or di-substitutedby aryl; and R and R₀, independently of one another, are each hydrogenor lower alkyl; or R and R₀ together, located at adjacent carbon atomsof the benzene ring, are a benzo group that is unsubstituted orsubstituted in the same way as phenyl in the definition of aryl below;aryl in the above definitions being phenyl that is unsubstituted orsubstituted by one or more substituents from the group consisting oflower alkyl, lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino,halogen, trifluoromethyl, carboxy, lower alkoxycarbonyl, (amino, loweralkylamino or di-lower alkylamino)-carbonyl, cyano, lower alkanoyl,benzoyl, lower alkylsulfonyl and (amino, lower alkylamino or di-loweralkylamino)-sulfonyl; heteroaryl in the above definitions being anaromatic heterocyclic radical from the group consisting of pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, thienyl,isoxazolyl, oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl,thiadiazolyl, pyridyl, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl,indolyl, isoindolyl, benzimidazolyl, benzotriazolyl, benzofuranyl,benzothienyl, benzoxazolyl, benzothiazolyl, benzoxadiazolyl,benzothiadiazolyl, quinolyl and isoquinolyl that is unsubstituted orsubstituted in the same way as phenyl in the definition of aryl above;and pharmaceutically acceptable salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 4-(2-tetrazolyl)methyl-benzonitrile,-   (2) 4-[α-(4-cyanophenyl)-(2-tetrazolyl)methyl]-benzonitrile,-   (3) 1-cyano-4-(1-tetrazolyl)methyl-naphthalene,-   (4) 4-[α-(4-cyanophenyl)(1-tetrazolyl)methyl]-benzonitrile.    (d) The compounds of formula I as defined in European Patent    Application No. 91810110.6. These are especially the compounds of    formula I

wherein X is halogen, cyano, carbamoyl, N-lower alkylcarbamoyl,N-cycloalkyl-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl,N-arylcarbamoyl, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy,wherein aryl is phenyl or naphthyl, each of which is unsubstituted orsubstituted by lower alkyl, hydroxy, lower alkoxy, halogen and/or bytrifluoromethyl; Y is a group —CH₂-A wherein A is 1-imidazolyl,1-(1,2,4-triazolyl), 1-(1,3,4-triazolyl), 1-(1,2,3-triazolyl),1-(1,2,5-triazolyl), 1-tetrazolyl or 2-tetrazolyl, or Y is hydrogen, R₁and R₁, independently of one another, are each hydrogen, lower alkyl ora group —CH₂-A as defined for Y, or R₁ and R₂ together are —(CH₂)_(n)—wherein n is 3, 4 or 5, with the proviso that one of the radicals Y, R₁and R₂ is a group —CH₂-A, with the further proviso that in a group—CH₂-A as a meaning of R₁ or R₂, A is other than 1-imidazolyl when X isbromine, cyano or carbamoyl, and with the proviso that in a group—CH.₂-A as a meaning of Y, A is other than 1-imidazolyl when X ishalogen or lower alkoxy, R₁ is hydrogen and R₂ is hydrogen or loweralkyl, and pharmaceutically acceptable salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 7-cyano-4-[1-(1,2,4-triazolyl)methyl]-2,3-dimethylbenzofuran,-   (2) 7-cyano-4-(1-imidazolylmethyl)-2,3-dimethylbenzofuran,-   (3) 7-carbamoyl-4-(1-imidazolylmethyl 2,3-dimethylbenzofuran,-   (4)    7-N-(cyclohexylmethyl)carbamoyl-4-(1-imidazolylmethyl)-2,3-dimethylbenzofuran.    (e) The compounds of formula I as defined in Swiss Patent    Application 1339/90-7.    These are especially the compounds of formula I

wherein the dotted line denotes an additional bond or no additionalbond, Az is imidazolyl, triazolyl or tetrazolyl bonded via a ringnitrogen atom, each of those radicals being unsubstituted or substitutedat carbon atoms by lower alkyl or by aryl-lower alkyl, Z is carboxy,lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-loweralkylcarbamoyl, N-arylcarbamoyl, cyano, halogen, hydroxy, lower alkoxy,aryl-lower alkoxy, aryloxy, lower alkyl, trifluoromethyl or aryl-loweralkyl, and R₁ and R₂, independently of one another, are each hydrogen,lower alkyl, lower alkoxy, hydroxy, halogen or trifluoromethyl; arylbeing phenyl or naphthyl each of which is unsubstituted or substitutedby one or two substituents from the group consisting of lower alkyl,lower alkoxy, hydroxy, halogen and trifluoromethyl; with the provisothat neither Z nor R₂ is hydroxy in the 8-position, and pharmaceuticallyacceptable salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 6-cyano-1-(1-imidazolyl)-3,4-dihydronaphthalene,-   (2) 6-cyano-1-[1-(1,2,4-triazolyl)]-3,4-dihydronaphthalene,-   (3) 6-chloro-1-(1-imidazolyl)-3,4-dihydronaphthalene,-   (4) 6-bromo-1-(1-imidazolyl)-3,4-dihydronaphthalene.    (f) The compounds of formula I as defined in Swiss Patent    Application 3014/90-0.    These are especially the compounds of formula I

wherein Z is a five-membered nitrogen-containing heteroaromatic tingselected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl,5-oxazolyl, 5-(1,2,3-thiadiazolyl), 5-(1,2,3-oxadiazolyl),3-(1,2,5-thiadiazolyl), 3-(1,2,5-oxadiazolyl), 4-isothiazolyl,4-isoxazolyl, 4-(1,2,3-thiadiazolyl), 4-(1,2,3-oxadiazolyl),2-(1,3,4-thiadiazolyl), 2-(1,3,4-oxadiazolyl), 5-(1,2,4-thiadiazolyl)and 5-(1,2,4-oxadiazolyl); R and R₀ are hydrogen; or R and R₀ togetherare a benzo group that is unsubstituted or substituted by lower alkyl,lower alkoxy, hydroxy, halogen or by trifluoromethyl; R₁ is hydrogen,hydroxy, chlorine or fluorine; R₃ is hydrogen; R₂ is hydrogen, loweralkyl or phenyl that is unsubstituted or substituted by lower alkyl,lower alkoxy, hydroxy, halogen, trifluoromethyl or by cyano; or R₁ andR₂ together are methylidene; or R₂ and R₃ together are —(CH₂)₃—; or R₁and R₂ and R₃ together are a group ═CH—(CH₂)₂— wherein the single boneis linked to the benzene ring; X is cyano; and X may also be halogenwhen R₂ and R₃ together are —(CH₂)₃— or R₁ and R₁ and R₃ together are agroup ═CH—(CH₂)₂—; and pharmaceutically acceptable salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1)    4-[α-(4-cyanophenyl)-α-hydroxy-5-isothiazolylmethyl]-benzonitrile.-   (2) 4-[α-(4-cyanophenyl)-5-isothiazolylmethyl]-benzonitrile,-   (3) 4-[α-(4-cyanophenyl)-5-thiazolylmethyl]-benzonitrile,-   (4) 1-(4-cyanophenyl)-1-(5-thiazolyl)-ethylene,-   (5) 6-cyano-1-(5-isothiazolyl)-3,4-dihydronaphthalene,-   (6) 6-cyano-1-(5-thiazolyl)-3,4-dihydronaphthalene.    (g) The compounds of formula VI as defined in Swiss Patent    Application 3014/90-0.    These are especially the compounds of formula VI

wherein Z is a five-membered nitrogen-containing heteroaromatic ringselected from the group 5-isothiazolyl, 5-thiazolyl, 5-isoxazolyl,5-oxazolyl, 5-(1,2,3-thiadiazolyl). 5-(1,2,3-oxadiazolyl)3-(1,2,5-thiadiazolyl), 3-(1,2,5-oxadiazolyl), 4-isothiazolyl.4-isoxazolyl, 4-(1,2,3-thiadiazolyl), 4-(1,2,3-oxadiazolyl),2-(1,3,4-thiadiazolyl), 2-(1,3,4-oxadiazolyl), 5-(1,2,4-thiadiazolyl)and 5-(1,2,4-oxadiazolyl); R and R₀ are each hydrogen; or R and R₀together are a benzo group that is unsubstituted or substituted by loweralkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; R₁ ishydrogen, hydroxy, chlorine or fluorine; R₃ is hydrogen; R₂ is hydrogen,lower alkyl or phenyl that is unsubstituted or substituted by loweralkyl, lower alkoxy, hydroxy, halogen, trifluoromethyl, aryl-loweralkoxy or by aryloxy; or R₁ and R₂ together are methylidene, and W₂ ishalogen, hydroxy, lower alkoxy, aryl-lower alkoxy or aryloxy; aryl ineach case being phenyl that is unsubstituted or substituted by loweralkyl, lower alkoxy, hydroxy, halogen or by trifluoromethyl; andpharmaceutically acceptable salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) bis(4,4′-bromophenyl)-(5-isothiazolyl)methanol,-   (2) bis(4,4′-bromophenyl)-(5-isothiazolyl)methane,-   (3) bis(4,4′-bromophenyl)-(5-thiazolyl)methanol,-   (4) bis(4,4′-bromophenyl)-(5-thiazolyl)methane,    (h) The compounds of formula I as defined in Swiss Patent    Application 3923/90-4.    These are especially the compounds of formula I

wherein Z is imidazolyl, triazolyl, tetrazolyl, pyrrolyl, pyrazolyl,indolyl, isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,pyridyl, pyrimidyl, pyrazinyl, pyridazinyl. triazinyl, quinolinyl orisoquinolinyl, all those radicals being bonded via their heterocyclicrings and all those radicals being unsubstituted or substituted by loweralkyl, hydroxy, lower alkoxy, halogen or by trifluoromethyl: R₁ and R₂,independently of one another, are each hydrogen or lower alkyl; or R₁and R₂ together are C₃-C₄ alkylene, or a benzo group that isunsubstituted or substituted as indicated below for aryl; R is hydrogen,lower alkyl, aryl or heteroaryl, and X is cyano, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-loweralkylenecarbamoyl; N,N-lower alkylenecarbamoyl interrupted by —O—, —S—or —NR″—, wherein R″ is hydrogen, lower alkyl or lower alkanoyl;N-cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)carbamoyl,N-cycloalkyl-lower alkylcarbamoyl, N-(lower alkyl-substitutedcycloalkyl)-lower alkylcarbamoyl, N-aryl-lower alkylcarbamoyl,N-arylcarbamoyl, N-hydroxycarbamoyl, hydroxy, lower alkoxy, aryl-loweralkoxy or aryloxy; and wherein X is also halogen when Z is imidazolyl,triazolyl, tetrazolyl, pyrrolyl, pyrazolyl, indolyl, isoindolyl,benzimidazolyl, benzopyrazolyl or benzotriazolyl; wherein aryl is phenylor naphthyl, these radicals being unsubstituted or substituted by from 1to 4 substituents from the group consisting of lower alkyl, loweralkenyl, lower alkynyl, lower alkylene (linked to two adjacent carbonatoms), C₃-C₈ cycloalkyl, phenyl-lower alkyl, phenyl; lower alkyl thatis substituted in turn by hydroxy, lower alkoxy, phenyl-lower alkoxy,lower alkanoyloxy, halogen, amino, lower alkylamino, di-loweralkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, loweralkylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano; hydroxy;lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenoxy, loweralkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy(linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-loweralkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-loweralkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower alkylsulfinyl,phenylsulfinyl, lower alkylsulfonyl, phenyl-lower alkylsulfonyl,phenylsulfonyl, halogen, nitro, amino, lower alkylamino, C₃-C₈cycloalkylamino, phenyl-lower alkylamino, phenylamino, di-loweralkylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl-loweralkylamino; lower alkyleneamino or lower alkyleneamino interrupted by—O—, —S— or —NR″— (wherein R″ is hydrogen, lower alkyl or loweralkanoyl); lower alkanoylamino, phenyl-lower alkanoylamino,phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl,phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-loweralkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N,N-loweralkylenecarbamoyl; N,N-lower alkylenecarbamoyl interrupted by —O—, —S—or —NR″—, wherein R″ is hydrogen, lower alkyl or lower alkanoyl;N-cycloalkylcarbamoyl, N-(lower alkyl-substituted cycloalkyl)-carbamoyl,N-cycloalkyl-lower alkylcarbamoyl,N-(lower alkyl-substituted cycloalkyl lower alkylcarbamoyl,N-hydroxycarbamoyl, N-phenyl-lower alkylcarbamoyl, N-phenylcarbamoyl,cyano, sulfo, lower alkoxysulfonyl, sulfamoyl, N-lower alkylsulfamoyl,N,N-di-lower alkylsulfamoyl and N-phenylsulfamoyl; the phenyl groupsoccurring in the substituents of phenyl and naphthyl in turn beingunsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy,halogen and/or by trifluoromethyl; wherein heteroaryl is indolyl,isoindolyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl,benzo[b]furanyl, benzo[b]thienyl, benzoxazolyl or benzothiazolyl, thoseradicals being unsubstituted or substituted by from 1 to 3 identical ordifferent substituents selected from lower alkyl, hydroxy, lower alkoxy,halogen, cyano and trifluoromethyl; and pharmaceutically acceptablesalts thereof.

Those compounds are especially the compounds of formula I whereto Z is1-imidazolyl, 1-(1,2,4-triazolyl), 1-(1,3,4-triazolyl),1-(1,2,3-triazolyl), 1-tetrazolyl, 2-tetrazolyl, 3-pyridyl, 4-pyridyl,4-pyrimidyl, 5-pyrimidinyl or 2-pyrazinyl; R₁ and R₂, independently ofone another, are each hydrogen or lower alkyl; or R.₁ and R₂ togetherare 1,4-butylene or a benzo group; R is lower alkyl; phenyl that isunsubstituted or substituted by cyano, carbamoyl, halogen, lower alkyl,trifluoromethyl, hydroxy, lower alkoxy or by phenoxy; or benzotriazolylor benzo[b]furanyl, the last two radicals being unsubstituted orsubstituted by from 1 to 3 identical or different substituents selectedfrom lower alkyl, halogen and cyano; and X is cyano or carbamoyl; andwherein X is also halogen when Z is 1-imidazolyl, 1-(1,2,4-triazolyl),1-(1,3,4-triazolyl), 1-(1,2,3-triazolyl), 1-tetrazolyl 2-tetrazolyl; andpharmaceutically acceptable salts thereof.

Individual compounds that may be given special mention here are:

-   (1)    4-[α-4-cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-benzonitrile,-   (2)    4-[α-(4-cyanophenyl)-α-fluoro-(2-tetrazolyl)methyl]-benzonitrile,-   (3)    4-[α-(4-cyanophenyl)-α-fluoro-(1-tetrazolyl)methyl]-benzonitrile,-   (4)    4-[α-(4-cyanophenyl)-α-fluoro-(1-imidazolyl)methyl]-benzonitrile,-   (5)    1-methyl-6-[α-(4-chlorophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-benzotriazole,-   (6) 4-[α-(4-cyanophenyl)-α-fluoro-1-(1,2,3-triazolyl)methyl]-benzo    nitrile,-   (7)    7-cyano-4-[α-(4-cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-2,3-dimethylbenzo[b]furan,-   (8) 4-[α-(4-bromophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl]-benzo    nitrile,-   (9) 4-[α-(4-cyanophenyl)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile,-   (10)    4-[α-(4-bromophenyl)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile,-   (11) 4-[α-(4-cyanophenyl)-α-fluoro-(3-pyridyl)methyl]-benzonitrile,-   (12)    7-bromo-4-[α-(4-cyanophenyl)-α-fluoro-(1-imidazolyl)methyl]-2,3-dimethylbenzo[b]furan,-   (13)    7-bromo-4-[α-(4-cyanophenyl)-α-fluoro-1-(1,2,4-triazolyl)methyl-]-2,3-dimethylbenzo[b]furan,-   (14)    4-[α-(4-cyanophenyl)-α-fluoro-(5-pyrimidyl)methyl)-benzonitrile,-   (15)    4-[α-(4-bromophenyl)-α-fluoro-(5-pyrimidyl)methyl]-benzonitrile,-   (16) 4-[α-(4-cyanophenyl)-1-(1,2,3-triazolyl)methyl]-benzonitrile,-   (17)    2,3-dimethyl-4-[α-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-7-cyano-benzo[b]furan,-   (18) 4-[α-(4-cyanophenyl)-(5-pyrimidyl)methyl]-benzonitrile,-   (19) 4-[α-(4-bromophenyl)-(5-pyrimidyl)methyl]-benzonitrile,-   (20)    2,3-dimethyl-4-[α-(4-cyanophenyl)-(1-imidazolyl)methyl]-7-bromo-benzo[b]furan,-   (21)    2,3-dimethyl-4-[α-(4-cyanophenyl)-1-(1,2,4-triazolyl)methyl]-7-bromo-benzo-[b]furan.    (i) The compounds of formula I as defined in EP-A-114 033. These are    especially the compounds of formula I

wherein R₁ is hydrogen, R₂ is hydrogen, sulfo, C₁-C₇ alkanoyl or C₁-C₇alkanesulfonyl and R₃ is hydrogen, or wherein R₁ is C₁-C₁₂ alkyl,C.₂-C₁₂ alkenyl, C₂-C₇ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C.₁₀ cycloalkenyl,C.₃3-C₆ cycloalkyl-C₁-C₄ alkyl, C₃-C₆ cycloalkyl-C.₂-C₄ alkenyl or C₃-C₆cycloalkenyl-C₁-C₄ alkyl, R₂ is hydrogen, C₁-C₇ alkyl, sulfo, C₁-C₇alkanoyl or C₁-C₇ alkanesulfonyl and R₃ is hydrogen or C₁-C₇ alkyl, andsalts of those compounds.

Individual compounds from that group that may be given special mentionare:

-   (1) 1-(4-aminophenyl)-3-methyl-3-azabicyclo[3.1.0]hexane-2,4-dione,-   (2)    1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.0]hexane-2,4-dione,-   (3)    1-(4-aminophenyl)-3-isobutyl-3-azabicyclo[3.1.0]hexane-2,4-dione,-   (4)    1-(4-aminophenyl)-3-n-heptyl-3-azabicyclo[3.1.0]hexane-2,4-dione,-   (5)    1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.0]hexane-2,4-dione.    (j) The compounds of formula I as defined in EP-A-166 692. These are    especially the compounds of formula I

wherein R₁ is hydrogen, alkyl having from 1 to 12 carbon atoms, alkenylhaving from 2 to 12 carbon atoms, lower alkynyl, cycloalkyl orcycloalkenyl each having from 3 to 10 carbon atoms, cycloalkyl-loweralkyl having from 4 to 10 carbon atoms, cycloalkyl-lower alkenyl havingfrom 5 to 10 carbon atoms, cycloalkenyl-lower alkyl having from 4 to 10carbon atoms, or aryl having from 6 to 12 carbon atoms or aryl-loweralkyl having from 7 to 15 carbon atoms, each of which is unsubstitutedor substituted by lower alkyl, hydroxy, lower alkoxy, acyloxy, amino,lower alkylamino, di-lower alkylamino, acylamino amino or by halogen, R₂is hydrogen, lower alkyl, sulfo, lower alkanoyl or lower alkanesulfonyl,sulfonyl, R₃ is hydrogen or lower alkyl and R₄ is hydrogen, lower alkyl,phenyl or phenyl substituted by —N(R₂)(R₃), and salts thereof, radicalsdescribed as “lower” containing up to and including 7 carbon atoms.

Individual compounds from that group that may be given special mentionare:

-   (1)    1-(4-aminophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione,-   (2) 1-(4-aminophenyl)-3-methyl-3-azabicyclo[3.1.1]heptane-2,4-dione,-   (3) 1-(4-aminophenyl)3-n-decyl-3-azabicyclo[3.1.1]heptane-2,4-dione,-   (4)    1-(4-aminophenyl)-3-cyclohexyl-3-azabicyclo[3.1.1]heptane-2,4-dione,-   (5)    1-(4-aminophenyl)-3-cyclohexylmethyl-3-azabicyclo[3.1.1]heptane-2,4-dione.    (k) The compounds of formula I as defined in EP-A-356 673. These are    especially the compounds of formula I

wherein W (α) is a 2-naphthyl or 1-anthryl radical, wherein each benzenering is unsubstituted or substituted by a substituent selected fromhalogen, hydroxy, carboxy, cyano and nitro; or (.beta.) is 4-pyridyl,2-pyrimidyl or 2-pyrazinyl, each of those radicals being unsubstitutedor substituted by a substituent selected from halogen, cyano, nitro,C₁-C₄ alkoxy and C₂-C₅ alkoxycarbonyl; and pharmaceutically acceptablesalts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 5-(2′-naphthyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine,-   (2) 5-(4′-pyridyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine.    (l) The compounds of formula I or Ia as defined in EP-A-337 929.    These are especially the compounds of formula I/Ia

wherein R₁ is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl,butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl,cyclohexylmethyl or benzyl, R₂ is benzyloxy, 3-bromo-, 4-bromo-,4-chloro-, 2,3-, 2,4-, 4,5- or 4,6-dichloro-benzyloxy, and R₃ is cyano;C₂-C₁₀ alkanoyl that is unsubstituted or mono- or poly-substituted byhalogen, methoxy, amino, hydroxy and/or by cyano; benzoyl that isunsubstituted or substituted by one or more substituents from the grouphalogen, C₁-C₄ alkyl, methoxy, amino, hydroxy and cyano; carboxy,(methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, N-isopropylcarbamoyl,N-phenylcarbamoyl, N-pyrrolidylcarbonyl, nitro or amino; and saltsthereof.

Individual compounds from that group that may be given special mentionare:

-   (1)    4-(2,4-dichlorobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile,-   (2) (4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)butyl]-phenyl pentyl    ketone,-   (3) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolylybutyl]-benzanilide,-   (4) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzoic acid,-   (5)    3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)butyl]-benzonitrile,-   (6) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic    acid methyl ester,-   (7) 3-(2,4-dichlorobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic    acid,-   (8) 3-(3-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzonitrile,-   (9) 4-(3-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile,-   (10) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzoic acid,-   (11) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzanilide,-   (12) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-phenyl pentyl    ketone,-   (13) 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzonitrile,-   (14) 3-(4-bromobenzyloxy)-4-[1-(1-imidazolyl)-butyl]-benzonitrile,-   (15)    4-nitro-2-[1-(1-imidazolyl)-butyl]-phenyl-(2,4-dichlorobenzyl)ether,-   (16)    4-amino-2-[1-(1-imidazolyl)-butyl]-phenyl-(2,4-dichlorobenzyl)ether,-   (17)    (2,4-dichlorobenzyl)-[2-(1-imidazolyl-methyl)-4-nitrophenyl]ether.    (m) The compounds of formula I as defined in EP-A-337 928. These are    especially the compounds of formula I

wherein R₁ is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl,butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl,cyclohexylmethyl or benzyl, R₂ is hydrogen, halogen, cyano, methyl,hydroxymethyl, cyanomethyl, methoxymethyl, pyrrolidinylmethyl, carboxy,(methoxy, ethoxy or butoxy)-carbonyl, carbamoyl, N-isopropylcarbamoyl,N-phenylcarbamoyl, N-pyrrolidylcarbonyl; C₂-C₁₀ alkanoyl that isunsubstituted or mono- or poly-substituted by halogen, methoxy, ethoxy,amino, hydroxy and/or by cyano; or benzoyl that is unsubstituted orsubstituted by one or more substituents from the group halogen, C₁-C₄alkyl, methoxy, ethoxy, amino, hydroxy and cyano, R₃ is hydrogen,benzyloxy, 3-bromo-, 4-bromo-, 4-chloro-, 2,3-, 2,4-, 4,5- or4,6-dichlorobenzyloxy, and X is —CH═N—; —CH═N(—O)— or —S—; and saltsthereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 5-[1-(1-imidazolyl)-butyl]-thiophene-2-carbonitrile,-   (2) 2-[1-(1-imidazolyl)-butyl]-thiophene-4-carbonitrile,-   (3) 2-[1-(1-imidazolyl)-butyl]-4-bromo-thiophene,-   (4) 2-[1-(1-imidazolyl)-butyl]-5-bromo-thiophene,-   (5) 5-[1-(1-imidazolyl)-butyl]-2-thienyl pentyl ketone,-   (6) 5-[1-(1-imidazolyl)-butyl]-2-thienyl ethyl ketone,-   (7)    5-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine-2-carbonitrile,-   (8)    3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine-2-carbonitrile,-   (9)    3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine-N-oxide,-   (10) 3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine.    (n) The compounds of formula I as defined in EP-A-340 153. These are    especially the compounds of formula I

wherein R₁ is hydrogen, methyl, ethyl, propyl, propenyl, isopropyl,butyl, hexyl, octyl, decyl, cyclopentyl, cyclohexyl, cyclopentylmethyl,cyclohexylmethyl or benzyl, and R₂ is a radical from the group methyl,ethyl, propyl, benzyl, phenyl and ethenyl that is substituted byhydroxy, cyano, methoxy, butoxy, phenoxy, amino, pyrrolidinyl, carboxy,lower alkoxycarbonyl or by carbamoyl; or R₂ is formyl or derivatisedformyl that can be obtained by reaction of the formyl group with anamine or amine derivative from the group hydroxylamine,O-methylhydroxylamine, O-ethylhydroxylamine, O-allylhydroxylamine,O-benzylhydroxylamine, O-4-nitrobenzyloxyhydroxylamine,O-2,3,4,5,6-pentafluorobenzyloxyhydroxylamine, semicarbazide,thiosemicarbazide, ethylamine and aniline; acetyl, propionyl, butyryl,valeryl, caproyl; benzoyl that is unsubstituted or substituted by one ormore substituents from the group halogen, C₁-C₄-alkyl, methoxy, amino,hydroxy and cyano; carboxy, (methoxy, ethoxy or butoxy)carbonyl,carbamoyl, N-isopropylcarbamoyl, N-phenylcarbamoyl orN-pyrrolidylcarbonyl; and salts thereof.

Individual compounds from that group that may be given special mentionare:

-   (1) 4-(1-(1-imidazolyl)-butyl)-benzoic acid methyl ester,-   (2) 4-(1-imidazolyl)-butyl)-benzoic acid butyl ester,-   (3) 4-(1-(1-imidazolyl)-butyl)-phenyl-acetonitrile,-   (4) 4-(1-(1-imidazolyl)-butyl)-benzaldehyde,-   (5) 4-(1-(1-imidazolyl)-butyl)-benzyl alcohol,-   (6) {4-[1-(1-imidazolyl)-butyl]-phenyl}-2-propyl ketone,-   (7) 4-[1-(1-imidazolyl)-butyl]-phenyl propyl ketone,-   (8) 4-[1-(1-imidazolyl)-butyl]-phenyl butyl ketone,-   (9) 4-[1-(1-imidazolyl)-butyl]-phenyl pentyl ketone,-   (10) 4-[1-(1-imidazolyl)-butyl]-phenyl hexyl ketone.    (o) The compounds of formula I as defined in DE-A-4 014 006. These    are especially the compounds of formula I

wherein A is an N-atom or a CH radical and W is a radical of the formula

wherein X is an oxygen or a sulfur atom or a —CH═CH— group and Y is amethylene group, an oxygen or a sulfur atom and Z is a —(CH₂)_(n)— groupwherein n=1, 2 or 3 and either a) R₃ in W is a hydrogen atom and R₁ andR₂, independently of one another, are each a hydrogen atom, a C₁— to C₁₀alkyl group or a C₃— to C₇ cycloalkyl group, or b) R₂ is as definedunder a) and R₁ together with R₃ forms a —(CH₂)_(m)— group wherein m=2,3, or 4, and their pharmaceutically acceptable addition salts withacids.

Individual compounds from that group that may be given special mentionare:

-   (1) 5-[1-(1-imidazolyl)-butyl]-1-indanone,-   (2) 7-[1-(1-imidazolyl)-butyl]-1-indanone,-   (3) 6-[1-(1-imidazolyl)-butyl]-1-indanone,-   (4) 6-(1-imidazolyl)-6,7,8,9-tetrahydro-1H-benz[e]inden-3(2H)-one,-   (5)    2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6-oxo-cyclopenta[b]-thiophene,-   (6) 6-[1-(1-imidazolyl)-butyl]-3,4-dihydro-2H-naphthalen-1-one,-   (7)    2-[1-(1-imidazolyl)-butyl]-6,7-dihydro-5H-benzo[b]thiophen-4-one,-   (8) 6-[1-(1-imidazolyl)-butyl]-2H-benzo[b]furan-3-one,-   (9) 5-[cyclohexyl-(1-imidazolyl)-methyl]-1-indanone,-   (10)    2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6H-benzo[b]thiophen-7-one,-   (11) 5-[1-(1-imidazolyl)-1-propyl-butyl]-1-indanone,-   (12)    2-[1-(1-imidazolyl)-butyl]-4,5-dihydro-6H-benzo[b]thiophen-7-one,-   (13)    2-[1-(1-imidazolyl)butyl]-4,5-dihydro-6-oxo-cyclopenta[b]-thiophene,-   (14) 5-(1-imidazolylmethyl)-1-indanone,-   (15) 5-[1-(1,2,4-triazolyl)-methyl]-1-indanone.    (p) The compounds of formula I as disclosed in DE-A-3 926 365. These    are especially the compounds of formula I

wherein W′ is a cyclopentylidene, cyclohexylidene, cycloheptylidene or2-adamantylidene radical, X is the grouping —CH═CH—, an oxygen or asulfur atom, and Y and Z, independently of one another, are each amethine group (CH) or a nitrogen atom, and their pharmaceuticallyacceptable addition salts with acids.

Individual compounds from that group that may be given special mentionare:

-   (1) 4-[1-cyclohexylidene-1-(imidazolyl)methyl]-benzonitrile,-   (2) 4-[1-cyclopentylidene-1-(imidazolyl)-methyl]-benzonitrile,-   (3) 4-[1-cycloheptylidene-1-(imidazolyl)-methyl]-benzonitrile,-   (4) 4-[2-adamantylidene-1-(imidazolyl)-methyl]-benzonitrile,-   (5) 4-[1-cyclohexylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile,-   (6) 4-[1-cyclopentylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile,-   (7) 4-[1-cycloheptylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile,-   (8) 4-[2-adamantylidene-1-(1,2,4-triazolyl)-methyl]-benzonitrile,-   (9) 4-[1-cyclohexylidene-1-(1,2,3-triazolyl)-methyl]-benzonitrile,-   (10) 4-[1-cyclopentylidene-1-(1,2,3-triazolyl)-methyl]-benzonitrile,-   (11)    5-[cyclohexylidene-1-imidazolylmethyl]-thiophene-2-carbonitrile.    (q) The compounds of formula I as defined in DE-A-3 740 125. These    are especially the compounds of formula I

wherein X is CH or N, R₁ and R₂ are identical or different and are eachphenyl or halophenyl, and R₃ is C₁-C₄ alkyl; C₁-C₄ alkyl substituted byCN, C₁-C₄ alkoxy, benzyloxy or by C₁-C₄ alkoxy-(mono-, di- ortri-)ethyleneoxy; C₁-C₄ alkoxy, phenyl; phenyl that is substituted byhalogen or by cyano; a C₅-C₇ cycloalkyl group that is optionallycondensed by benzene, or is thienyl, pyridyl or 2- or 3-indolyl; andacid addition salts thereof.

An individual compound from that group that may be given special mentionis:

-   (1)    2,2-bis(4-chlorophenyl)-2-(1H-imidazol-1-yl)-1-(4-chlorobenzoyl-amino)    ethane.    (r) The compounds of formula I as defined in EP-A-293 978. These are    especially the compounds of formula I

pharmaceutically acceptable salts and stereochemically isomeric formsthereof, wherein -A₁=A₂-A₃=A₄- is a divalent radical selected from—CH═N—CH═CH—, —CH═N—CH═N— and —CH═N—N═CH—. R is hydrogen or C₁-C₆ alkyl;R₁ is hydrogen, C₁-C₁₀ alkyl, C₃-C₇ cycloalkyl. Ar₁, Ar₂—C₁-C₆ alkyl,C₂-C₆ alkenyl or C₂-C₆ alkynyl: R₂ is hydrogen; C₁-C₁₀ alkyl that isunsubstituted or substituted by Ar₁; C₃-C₇ cycloalkyl, hydroxy, C₁-C₆alkoxy, Ar₁, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,bicyclo[2.2.1]heptan-2-yl, 2,3-dihydro-1H-indenyl,1,2,3,4-tetrahydronaphthyl, hydroxy; C₂-C₆ alkenyloxy that isunsubstituted or substituted by Ar₂; C₂-C₆ alkynyloxy; pyrimidyloxy;di(Ar₂)methoxy, (1-C₁-C₄ alkyl-4-piperidinyl)oxy, C₁-C₁₀ alkoxy; orC₁-C₁₀ alkoxy that is substituted by halogen, hydroxy, C₁-C₆ alkyloxy,amino, mono- or di-(C₁-C₆ alkyl)amino, trifluoromethyl, carboxy, C₁-C₆alkoxycarbonyl, Ar.sub.I, Ar₂—O—, Ar₂—S—, C₃-C₇ cycloalkyl,2,3-dihydro-1,4-benzodioxinyl, 1H-benzimidazolyl, C₁-C₄alkyl-substituted 1H-benzimidazolyl, (1,1′-biphenyl)-4-yl or by2,3-dihydro-2-oxo-1H-benzimidazolyl; and R₃ is hydrogen, nitro, amino,mono- or di-(C₁-C₆ alkyl)amino, halogen, C₁-C₆ alkyl, hydroxy or C₁-C₆alkoxy; wherein Ar₁ is phenyl, substituted phenyl, naphthyl, pyridyl,aminopyridyl, imidazolyl, triazolyl, thienyl, halothienyl, furanyl,C₁-C₆ alkylfuranyl, halofuranyl or thiazolyl; wherein Ar₂ is phenyl,substituted phenyl or pyridyl; and wherein “substituted phenyl” isphenyl that is substituted by up to 3 substituents in each case selectedindependently of one another from the group consisting of halogen,hydroxy, hydroxymethyl, trifluoromethyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,C₁-C₆ alkoxycarbonyl, carboxy, formyl, hydroxyiminomethyl, cyano, amino,mono- and di-(C₁-C₆ alkyl)amino and nitro.

Individual compounds from that group that may be given special mentionare:

-   (1) 6-[(1H-imidazol-1-yl)-phenylmethyl]-1-methyl-1H-benzotriazole,-   (2)    6-[(4-chlorophenyl)(1H-1,2,4-triazol-1-yl)methyl]-1-methyl-1H-benzotriazole.    (s) The compounds of formula II as defined in EP-A-250 198,    especially-   (1) 2-(4-chlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol,-   (2) 2-(4-fluorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol,-   (3)    2-(2-fluoro-4-trifluoromethylphenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol,-   (4) 2-(2,4-dichlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)ethanol,-   (5) 2-(4-chlorophenyl)-1,1-di(1,2,4-triazol-1-ylmethyl)-ethanol,-   (6) 2-(4-fluorophenyl)-1,1-di(1,2,4-triazol-1-yl-methyl)ethanol.    (t) The compounds of formula I as defined in EP-A-281 283,    especially-   (1)    (1R*2R*)-6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-(1H-1,2,4-triazol-1-yl-methyl)naphthalene,-   (2)    (1R*,2R*)-6-fluoro-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-(1H-imidazolylmethyl)-naphthalene,-   (3) (1R*,2R*)- and    (1R*,2S*)-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-1-(1H-1,2,4-tetrahydro-1-(1H-1,2,4-triazol-1-ylmethyl)naphthalene-6-carbonitrile,-   (4) (1R*,2R*)- and    (1R*,2S*)-2-(4-fluorophenyl)-l,2,3,4-tetrahydro-1-(1H-imidazolylmethyl)naphthalene-6-carbonitrile,-   (5) (1R*,2R*)- and    (1R*,2S*)-1,2,3,4-tetrahydro-1-(1H-1,2,4-triazol-1-ylmethyl)-naphthalene-2,6-dicarbonitrile,-   (6) (1R*,2R*)- and    (1R*,2S*)-1,2,3,4-tetrahydro-1-(1H-imidazol-1-ylmethyl)naphthalene-2,6-dicarbonitrile,-   (7)    (1R*,2S*)-2-(4-fluorophenyl)-1,2,3,4-tetrahydro-1-(5-methyl-1H-imidazolyl-methyl)naphthalene-6-carbonitrile.    (u) The compounds of formula I as defined in EP-A-296 749,    especially-   (1)    2,2′-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]di(2-methylpropiononitrile),-   (2)    2,2′-[5-(imidazol-1-ylmethyl)-1,3-phenylene]di(2methylpropiononitrile),-   (3)    2-[3-(1-hydroxy-1-methylethyl)-5-(5H-1,2,4-triazol-1-ylmethyl)phenyl]-2-methylpropiononitrile,-   (4)    2,2′-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-1,3-phenylene]di(2-trideuteriomethyl-3,3,3-trideuteriopropiononitrile),-   (5)    2,2′-[5-dideuterio(1H-1,2,4-triazol-1-yl)methyl-3-phenylene]di(2methylpropiononitrile).    (v) The compounds of formula I as defined in EP-A-299 683,    especially-   (1) (Z)-α-(1,2,4-triazol-1-ylmethyl)stilbene-4,4′-dicarbonitrile,-   (2)    (Z)-4′-chloro-α-(1,2,4-triazol-1-ylmethyl)stilbene-4-carbonitrile,-   (3)    (Z)-α-(1,2,4-triazol-1-ylmethyl)-4′-(trifluoromethyl)stilbene-4-carbonitrile,-   (4)    (E)-.beta.-fluoro-α-(1,2,4-triazol-1-ylmethyl)stilbene-4,4′-dicarbonitrile,-   (5) (Z)4′-fluoro-α-(imidazol-1-ylmethyl)stilbene-4-carbonitrile,-   (6)    (Z)-2′,4′-dichloro-α-(imidazol-1-ylmethyl)stilbene-4-carbonitrile,-   (7) (Z)-4′-chloro-α-(imidazol-1-ylmethyl)stilbene-4-carbonitrile,-   (8) (Z)-α-(imidazol-1-ylmethyl)stilbene-4,4′dicarbonitrile,-   (9) (Z)-α-(5-methylimidazol-1-ylmethyl)stilbene-4,4′-dicarbonitrile,-   (10)    (Z)-2-[2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)propenyl]pyridine-5-carbonitrile.    (w) The compounds of formula I as defined in EP-A-299 684,    especially-   (1) 2-(4-chlorobenzyl)-2-fluoro-1,3-di(1,2,4-triazol-1-yl)propane,-   (2)    2-fluoro-2-(2-fluoro-4-chlorobenzyl)-1,3-di(1,2,4-triazol-1-yl)propane,-   (3)    2-fluoro-2-(2-fluoro-4-trifluoromethylbenzyl)-1,3-di(1,2,4-triazol-1-yl)propane,-   (4)    3-(4-chlorophenyl)-1-(1,2,4-triazol-1-yl)-2-(1,2,4-triazol-1-ylmethyl)butan-2-ol,-   (5)    2-(4-chloro-α-fluorobenzyl)-1,3-di(1,2,4-triazol-1-yl)propan-2-ol,-   (6) 2-(4-chlorobenzyl)-1,3-bis(1,2,4-triazol-1-yl)propane,-   (7)    4-[2-(4-chlorophenyl)-1,3-di(1,2,4-triazol-1-ylmethyl)ethoxymethyl]-benzonitrile,-   (8)    1-(4-fluorobenzyl)-2-(2fluoro-4-trifluoromethylphenyl)-1,3-di(1,2,4-triazol-1-yl)-propan-2-ol,-   (9)    2-(4-chlorophenyl)-1-(4-fluorophenoxy)-1,3-di(1,2,4-triazol-1-yl)propan-2-ol,-   (10)    1-(4-cyanobenzyl)-2-(2,4-difluorophenyl)-1,3di(1,2,4-triazol-1-yl)propan-2-ol,-   (11)    2-(4-chlorophenyl)-1-phenyl-1,3-di(1,2,4-triazol-1-yl)propan-2-ol.    (x) The compounds as defined in claim 1 of EP-A-316 097, especially-   (1)    1,1-dimethyl-8-(1H-1,2,4-triazol-1-ylmethyl)-2(1H)-naphtho[2,1-b]furanone,-   (2)    1,2-dihydro1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]-furan-7-carbonitrile,-   (3)    1,2-dihydro-1,1-dimethyl-2-oxo-8-(1H-1,2,4-triazol-1-ylmethyl)naphtho[2,1-b]-furan-7-carboxamide,-   (4)    1,2-dihydro-1,1-dimethyl-2-oxo-8-[di(1H-1,2,4-triazol-1-yl)methyl]naphtho[2,1-b]-furan-7-carbonitrile.    (y) The compounds of formula I as defined in EP-A-354 689,    especially-   (1) 4-[2-(4-cyanophenyl)-3-(1,2,4-triazol-1-yl)propyl]benzonitrile,-   (2) 4-[1-(4-chlorobenzyl)-2-(1,2,4-triazol-1-yl)ethyl]benzonitrile,-   (3)    4-[2-(1,2,4-triazol-1-yl)-1-(4-trifluoromethyl]benzyl)ethyl]benzonitrile,-   (4)    4-[2-(1,2,4-triazol-1-yl)-1-(4-[trifluoromethoxy]benzyl)ethyl]benzonitrile.    (z) The compounds of formula (1) as defined in EP-A-354 683,    especially-   (1)    6-[2-(4-cyanophenyl)3-(1,2,4-triazol-1-yl)-propyl]nicotinonitrile,-   (2)    4-[1-(1,2,4-triazol-1-yl-methyl)2-(5[trifluoromethyl]pyrid-2-yl)ethyl]benzonitrile.

Examples of steroidal aromatase inhibitors that may be mentioned are:

(aa) The compounds of formula I as defined in EP-A-181 287. These areespecially the compounds of formula I

wherein R is hydrogen, acetyl, heptanoyl or benzoyl. An individualcompound from that group that may be given special mention is:

-   (1) 4-hydroxy-4-androstene-3,17-dione.    (ab) The compounds as defined in the claims of U.S. Pat. No.    4,322,416, especially 10-(2-propynyl)-oestr-4-ene-3,17-dione.    (ac) The compounds as defined in the claims of DE-A-3 622 841,    especially 6-methyleneandrosta-1,4-diene-3,17-dione.    (ad) The compounds as defined in the claims of GB-A-2 17 1100,    especially 4-amino-androsta-1,4,6-triene-3,17-dione.

Also: (ae) androsta-1,46-triene-3,17-dione.

The content of the patent applications mentioned under (a) to (z) and(aa) to (ad), especially the subgroups of compounds disclosed thereinand the individual compounds disclosed therein as examples, have beenincorporated by reference into the disclosure of the presentapplication.

The general terms used hereinbefore and hereinafter to define thecompounds have the following meanings:

Organic radicals designated by the term “lower” contain up to andincluding 7, preferably up to and including 4, carbon atoms.

Acyl is especially lower alkanoyl.

Aryl is, for example, phenyl or 1- or 2-naphthyl, each of which isunsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy,lower alkanoyloxy, amino, lower alkylamino, di-lower alkylamino, loweralkanoylamino or by halogen.

Pharmaceutically acceptable salts of the above-mentioned compounds are,for example, pharmaceutically acceptable acid addition salts orpharmaceutically acceptable metal or ammonium salts.

Pharmaceutically acceptable acid addition salts are especially thosewith suitable inorganic or organic acids, for example strong mineralacids, such as hydrochloric acid, sulfuric acid or phosphoric acid, ororganic acids, especially aliphatic or aromatic carboxylic or sulfonicacids, for example formic, acetic, propionic, succinic, glycolic,lactic, hydroxysuccinic, tartaric, citric, maleic, fumaric,hydroxymaleic, pyruvic, phenylacetic, benzoic, 4-aminobenzoic,anthranilic, 4-hydroxybenzoic, salicylic, 4-aminosalicylic, pamoic,gluconic, nicotinic, methanesulfonic, ethanesulfonic,halobenzenesulfonic, p-toluenesulfonic, naphthalenesulfonic, sulfanilicor cyclohexylsulfamic acid; or with other acidic organic substances, forexample ascorbic acid. Pharmaceutically acceptable salts may also beformed, for example, with amino acids, such as arginine or lysine.

Compounds containing acid groups, for example a free carboxy or sulfogroup, can also form pharmaceutically acceptable metal or ammoniumsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium, magnesium or calcium salts, also ammonium saltsderived from ammonia or suitable organic amines. Them come intoconsideration especially aliphatic, cycloaliphatic,cycloaliphatic-aliphatic or araliphatic primary, secondary or tertiarymono-, di- or poly-amines, such as lower alkylamines, for example di- ortri-ethylamine, hydroxy-lower alkylamines, for example2-hydroxyethylamine, bis(2-hydroxyethyl)amine ortris(2-hydroxyethyl)amine, basic aliphatic esters or carboxylic acids,for example 4-aminobenzoic acid 2-diethylaminoethyl ester, loweralkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, forexample dicyclohexylamine, benzylamines, for exampleN,N′-dibenzylethylenediamine; also heterocyclic bases, for example ofthe pyridine type, for example pyridine, collidine or quinoline. Ifseveral acidic or basic groups are present, mono- or poly-salts can beformed. Compounds according to the invention having an acidic and abasic group may also be in the form of internal salts, i.e. in the formof zwitterions and another part of the molecule in the form of a normalsalt.

In the case of the above-mentioned individual compounds thepharmaceutically acceptable salts are included in each case insofar asthe individual compound is capable of salt formation.

The compounds listed, including the individual compounds mentioned, bothin free form and in salt form, may also be in the form of hydrates, ortheir crystals may include, for example, the solvent used forcrystallisation. The present invention relates also to all those forms.

Many of the above-mentioned compounds, including the individualcompounds mentioned, contain at least one asymmetric carbon atom. Theycan therefore occur in the form of R- or S-enantiomers and asenantiomeric mixtures thereof, for example in the form of a racemate.The present invention relates to the use of all those forms and to theuse of all further isomers, and of mixtures of at least 2 isomers, forexample mixtures of diastereoisomers or enantiomers which can occur whenthere are one or more further asymmetric centres in the molecule. Alsoincluded are, for example, all geometric isomers, for example cis- andtrans-isomers, that can occur when the compounds contain one or moredouble bonds.

Pharmaceutical Formulations

The pharmaceutical compositions that can be prepared according to theinvention are compositions for enteral, such as peroral or rectaladministration, also for transdermal or sublingual administration, andfor parenteral, for example intravenous, subcutaneous and intramuscular,administration. Suitable unit dose forms, especially for peroral and/orsublingual administration, for example dragees, tablets or capsules,comprise preferably from approximately 0.01 mg to approximately 20 mg,especially from approximately 0.1 mg to approximately 10 mg, of one ofthe above-mentioned compounds or of a pharmaceutically acceptable saltthereof, together with pharmaceutically acceptable carriers. Thepreferred form of administration is oral. The proportion of activeingredient in such pharmaceutical compositions is generally fromapproximately 0.001% to approximately 60%, preferably from approximately0.1% to approximately 20%.

Suitable excipients for pharmaceutical compositions for oraladministration are especially fillers, such as sugars, for examplelactose, saccharose, mannitol or sorbitol, cellulose preparations and/orcalcium phosphates, for example tricalcium phosphate or calcium hydrogenphosphate, and binders, such as starches, for example corn, wheat, riceor potato starch, gelatin, tragacanth, methylcellulose and/orhydroxypropylcellulose, disintegrators, such as the above-mentionedstarches, also carboxymethyl starch, cross-linked polyvinylpyrrolidone,agar, alginic acid or a salt thereof, such as sodium alginate, and/orcellulose, for example in the form of crystals, especially in the formof microcrystals, and/or flow regulators and lubricants, for examplesilicic acid, talc, stearic acid or salts thereof, such as magnesium orcalcium stearate, cellulose and/or polyethylene glycol.

Dragee cores can be provided with suitable, optionally enteric,coatings, there being used inter alia concentrated sugar solutions whichmay comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycoland/or titanium dioxide, or coating solutions in suitable solvents orsolvent mixtures, or, for the preparation of enteric coatings, solutionsof suitable cellulose preparations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate.

Other orally administrable pharmaceutical compositions are dry-filledcapsules consisting of gelatin, and also soft sealed capsules consistingof gelatin and a plasticiser, such as glycerol or sorbitol. Thedry-filled capsules may contain the active ingredient in the form ofgranules, for example in admixture with fillers, such as lactose,binders, such as starches, and/or glidants, such as talc or magnesiumstearate, and, if desired, stabilisers. In soft capsules, the activeingredient is preferably dissolved or suspended in suitable oilyexcipients, such as fatty oils, paraffin oil or liquid polyethyleneglycols, to which stabilisers and/or anti-bacterial agents may also beadded. There may also be used capsules that are easily bitten through,in order to achieve by means of the sublingual ingestion of the activeingredient that takes place as rapid an action as possible.

Suitable rectally or transvaginally administrable pharmaceuticalcompositions are, for example, suppositories that consist of acombination of the active ingredient with a suppository base. Suitablesuppository bases are, for example, natural or synthetic triglycerides,paraffin hydrocarbons, polyethylene glycols or higher alkanols. Theremay also be used gelatin rectal capsules, which contain a combination ofthe active ingredient with a base material. Suitable base materials are,for example, liquid triglycerides, polyethylene glycols or paraffinhydrocarbons.

Suitable formulations for transdermal administration comprise the activeingredient together with a carrier. Advantageous carriers includeabsorbable pharmacologically acceptable solvents that serve tofacilitate the passage through the skin of the host. Transdermal systemsare usually in the form of a bandage that comprises a support, a supplycontainer containing the active ingredient, if necessary together withcarriers, optionally a separating device that releases the activeingredient onto the skin of the host at a controlled and establishedrate over a relatively long period of time, and means for securing thesystem to the skin.

Suitable for parenteral administration are especially aqueous solutionsof an active ingredient in water-soluble form, for example in the formof a water-soluble salt, and also suspensions of active ingredient, suchas corresponding oily injection suspensions, there being used suitablelipophilic solvents or vehicles, such as fatty oils, for example sesameoil, or synthetic fatty acid esters, for example ethyl oleate, ortriglycerides, or aqueous injection suspensions that compriseviscosity-increasing substances, for example sodiumcarboxymethylcellulose, sorbitol and/or dextran, and, optionally,stabilisers.

Dyes or pigments may be added to the pharmaceutical compositions,especially to the tablets or dragee coatings, for example foridentification purposes or to indicate different doses of activeingredient.

The pharmaceutical compositions of the present invention can be preparedin a manner known per se, for example by means of conventional mixing,granulating, confectioning, dissolving or lyophilising processes. Forexample, pharmaceutical compositions for oral administration can beobtained by combining the active ingredient with solid carriers,optionally granulating a resulting mixture, and processing the mixtureor granules, if desired or necessary after the addition of suitableexcipients, to form tablets or dragee cores.

The term “improving” as used herein in connection with an effect onimplantation or pregnancy includes any measurable improvement orincrease in frequency of occurrence of implantation or pregnancy in anindividual for example when compared with the level or frequency ofoccurrence of implantation or pregnancy in one or more non-treatedpatients or when compared to the level or frequency of occurrence ofimplantation or pregnancy in the same patient observed at an earliertime point (e.g. comparison with a “base line” level). Preferably theimprovement or increase will be a statistically significant one,preferably with a probability value of <0.05. Methods of determining thestatistical significance of results are well known and documented in theart and any appropriate method may be used.

EXAMPLES

The invention that is claimed is described in detail in the followingExamples, which are intended merely to illustrate the invention, and inno way to represent a limitation thereof.

Example 1

This was a prospective controlled study that included a study group, thepatients of which received letrozole (2.5 mg/day from (day 3 to 7 of themenstrual cycle) in addition to FSH and a control group that receivedFSH only. The study group included 12 unexplained infertility patients.The control group-consisted of 55 unexplained infertility patients. Allpatients received recombinant or highly purified FSH (50-150 IU/daystarting on day 3 to 7 until day of hCG (10,000 IU) that was given when2 leading follicles were >2 cm). The FSH regimen was based on thepatient's clinical profile. Patients were not randomized. All patientshad intrauterine insemination. There was no statistically significantdifference between the study and control groups as regards age, weight,infertility duration, number of prior insemination cycles, semenparameters or type of FSH.

The FSH needed was statistically significantly lower when letrozole wasused in both study group compared with the control group. However, therewas no significant difference, in number of follicles >1.8 cm.,endometrial thickness, LH level or day of hCG administration. Estradiollevel in letrozole/FSH cycles was in the normal physiological range,which was unexpected as higher levels are normally associated withincreased follicle production. Pregnancy rate in the study group was 25%versus 18% in the control group. This is indicative of a positive trendin this rate. The study contained too few patients and cycles for theresults to be considered to be statistically significant.

TABLE 1 Letrozole + Treatment FSH FSH only P value Pregnancy rate 25%18% NS Total FSH 585 1320 <0.05 dose/cycle (IU) Day of hCG 12 12 NSadministration Endometrial 11.5 12.1 NS thickness (on hCG day) Follicle(>1.8 cm) 3.4 3.2 NS on hCG day Estradiol on hCG 2130 3140 <0.05 day(pmol/L) Estradiol/mature 626 969 <0.05 follicle (pmol/L) LH on hCG day16.3 18.3 NS (IU/L) NS = not significant

Example 2

Fifteen patients who either failed to ovulate (6 cycles) or ovulatedwith an endometrial thickness <5 mm (24 cycles) in response to CC andwho did not conceive were given letrozole orally, at least two monthsafter the last CC cycle, in a dose of 2.5 to 5 mg/day, from day 3 to 7or 5 to 9 of the menstrual cycle. HCG 10,000 IU was given to triggerovulation. CC was given in a dose of 50-100 mg on days 3-7 or 5-9.

Fifteen patients completed 17 letrozole cycles. Ovulation occurred in 13cycles (77%) and pregnancy in 5 out of 15 patients (33%). The followingtable shows summary of CC and letrozole cycles.

TABLE 2 Mean Range Median Treatment Letrozole CC P Letrozole CCLetrozole CC Day of hCG 14.5 12.6 S 11-18 11-16 15 12 administrationNumber of Days from 6.7 4.4 S 2-9 2-7 7 4 last letrozole tablet to hCGday Endometrial Thickness 0.8 0.5 S 0.6-1.1 0.4-0.8 0.8 0.4 (Cm.)Follicles > 1.5 Cm 2.4 1.9 NS 1-3 1-5 2 2 on day of hCG administrationEstradiol (pmol/L) 1016 2145 S  107-2347  362-5210 901 1668 on day ofhCG administration Estradiol per mature 392 1278 S 107-837  177-2404 2891486 follicle (pmol/L) LH on day of hCG 16 16 NS 3.1-66   3-66 8.2 8administration (IU/L) P value (<0.005 = significant) S = Significant NS= Not Significant

These results illustrate the improvement letrozole offers over CC inrelation to endometrial thickness and reduced estradiol levels. Theresults suggest improved pregnancy levels.

Example 3

This example demonstrates the effect of letrozole alone in a single doseform of administration. The estradiol levels in 9 treatment cycles in 7infertile patients (3 with PCOS and 4 with unexplained infertility)undergoing ovarian stimulation and cycle monitoring for IUI who receiveda single 20 mg dose of letrozole on day 3 of the cycle. Follicledevelopment was monitored by transvaginal ultrasound and by serum levelsof estradiol and LH. Pregnancy was achieved in one patient. The meanestradiol level on the day of hCG was 831 pmol/L and the mean estradiollevel per mature follicle was 390 pmol/L, almost exactly the same asseen with a 5-day daily dose of letrozole illustrated in the previousexample.

TABLE 3 Letrozole single- dose cycles Day of hCG administration  12.9(2.9) Endometrial thickness on hCG  0.9 (0.11) day (cm) Follicles > 1.5cm  2.29 (1.3) Estradiol on hCG day (pmol/L) 831 (359) Estradiol/maturefollicle 390 (74) (pmol/L) LH (IU/L)  19.1 (12.7)

Example 4 Superovulation for IUI with Letrozole and FSH

Patient Group: 19 Women with unexplained fertility, 6 with PCOS, 2 withendometriosis and one with male factor

Protocol: Study group received Letrozole (2.5 to 5 mg/day, days 3 to 7)and FSH (dose adjusted to need, starting on day 3, 5 or 7); hCG (10,000bolus). Control group received FSH alone.

Fertilisation Method: IUI

Endpoints: Pregnancy rate, endometrial thickness, follicles >1.5 cm onhCG day, estradiol on hCG day, total FSH dose

Results: Pregnancy rate with Letrozole and FSH was 38% (not reported forFSH alone), endometrial thickness was the same in both groups, number offollicles >1.5 cm was the same, estradiol was 45% lower in Letrozolegroup, total FSH dose was decreased by 77% in Letrozole group

Example 5 Letrozole for Ovulation Induction: Summary

Patient Group: PCOS and unexplained infertility undergoing IUI.

Protocol: Study group 1 PCOS patients received Letrozole (2.5 to 5mg/day, days 3 to 7); hCG bolus 10,000 I.U. Control group 1 PCOSpatients received CC (50-100 mg/day, days 3 to 7 or days 5 to 9); hCGbolus 10,000 I.U. Study group 2 unexplained infertility patientsreceived Letrozole (2.5 mg/day, days 3 to 7) plus FSH (50-150 I.U.,starting on days 3 to 7 until hCG); hCG bolus 10,000 I.U. Control group2 unexplained infertility patients received CC (50-100 mg/day, days 3 to7) plus FSH (50-150 I.U., starting on day 3 to 7 until hCG); hCG bolus10,000 I.U.Fertilisation Method: Timed intercourse or IUIEndpoints: Pregnancy rate, ovulation rate, endometrial thickness,follicles >1.5 cm on hCG day, oestradiol on hCG day.Results: Pregnancy rate was higher with Letrozole VS CC in both kinds ofregimen, ovulation rate was higher with Letrozole VS CC in PCOS patients(not reported for unexplained fertility), endometrial thickness wasbetter with Letrozole.

While the invention has been described with particular reference tocertain embodiments thereof, it will be understood that changes andmodifications may be made by those of ordinary skill in the art withinthe scope and spirit of the following claims.

In the claims, the word “comprising” means “including the followingelements (in the body), but not excluding others”; the phrase“consisting of” means “excluding more than traces of other than therecited ingredients”; and the phrase “consisting essentially of” means“excluding unspecified ingredients which materially affect the basiccharacteristics of the composition”.

REFERENCES

-   ¹Hadi, F. H., Chantler, E., Anderson, E. et al. (1994) Ovulation    induction and endometrial steroid receptors. Hum. Reprod., 9,    2405-2410.-   ²Paulson, R. J., Sauer, M. V. and Lobo, R. A. (1990) Factors    affecting embryo implantation after human in vitro fertilization: a    hypothesis. Am. J. Obstet. Gynecol., 163, 2020-2023; Simón, C.,    Cano, F., Valbueña, D. et al. (1995) Clinical evidence for a    detrimental effect on uterine receptivity of high serum oestradiol    concentrations in high and normal responder patients. Hum. Reprod.,    10, 2432-2437; Ng. E. H. Y., Yeung, W. S. B., Lau, E. Y. and    Ho, P. C. (2000) High serum oestradiol concentration in fresh IVF    cycles do not impair implantation and pregnancy rates in subsequent    frozen-thawed embryo transfer cycles. Hum. Reprod., 15, 250-255.-   ³Ng, Yeung, Lau and Ho, High serum oestradiol concentration in fresh    IVF cycles do not impair implantation and pregnancy rates in    subsequent frozen-thawed embryo transfer cycles. p. 15, 250-255.-   ⁴Ghazala Sikandar Basir G S, Wai-sum O, Ng E H and Ho P C.    Morphometric analysis of peri-implantation endometrium in patients    having excessively high oestradiol concentrations after ovarian    stimulation. Hum Reprod, 2001; 16(3): 435-40; Forman, R., Fries, N.,    Testart, J. et al. (1988) Evidence for an adverse effect of elevated    serum estradiol concentration on embryo implantation. Fertil.    Steril., 49, 118-112.-   ⁵Garcia, J. E., Acosta, A. A., Hsiu, J. G. and    Jones, H. W. J. (1984) Advanced endometrial maturation after    ovulation induction with human menopausal gonadotropin/human    chorionic gonadotropin for in vitro fertilization. Fertil. Steril.,    41, 31-35; Graf, M. J., Reyniak, J. V., Battle, M. P. and    Laufer, N. (1988) Histologic evaluation of the luteal phase in women    following follicle aspiration for oocyte retrieval. Fertil. Steril.,    49, 616-619.-   ⁶Sterzik, K., Dallenbach, C., Schneider, V. et al. (1988) In vitro    fertilization: the degree of endometrial insufficiency varies with    the type of ovarian stimulation. Fertil. Steril., 50, 457-462;    Seif, M. W., Pearson, J. M., Ibrahim, Z. H. et al. (1992)    Endometrium in in-vitro fertilization cycles: morphological and    functional differentiation in the implantation phase. Hum. Reprod.,    7, 6-11.-   ⁷Kolb, B. A., Najmabadi, S. and Paulson, R. J. (1997)    Ultrastructural characteristics of the luteal phase endometrium in    patients undergoing controlled ovarian stimulation. Fertil. Steril.,    67, 625-630.-   ⁸Macrow, P. J., Li, T. C., Seif, M. W. et al. (1994) Endometrial    structure after superovulation: a prospective controlled study.    Fertil. Steril., 61, 696-699.-   ⁹Noci, I., Borri, P., Coccia, M. E. et al. (1997) Hormonal patterns,    steroid receptors and morphological pictures of endometrium in    hyperstimulated IVF cycles. Eur. J. Obstet. Gynecol. Reprod. Biol.,    75, 215-220.-   ¹⁰Forman, Fries and Testart, Evidence for an adverse effect of    elevated serum estradiol concentration on embryo implantation. p.    49, 118-112.-   ¹¹Geeta Nargund, John Waterstone, J. Martin Bland, Zoe Philips, John    Parsons, and Stuart Campbell Cumulative conception and live birth    rates in natural (unstimulated) IVF cycles Hum. Reprod. 2001 16:    259-262.-   ¹²Valbuena D, Martin J, de Pablo J L, Remohi J, Pellicer A, Simon C.    Increasing levels of estradiol are deleterious to embryonic    implantation because they directly affect the embryo. Fertil Steril    2001; 76:962-8.-   ¹³Simón, C., Garcia, V. J., Valbueña, D. et al. (1998) Increasing    uterine receptivity by decreasing estradiol levels during the    preimplantation period in high responders with the use of a    follicle-stimulating hormone step-down regimen. Fertil. Steril., 70,    234-239.-   ¹⁴Tortoriello D V, McGovern P G, Colon J M, Skurnick J H, Lipetz K,    Santoro N. “Coasting” does not adversely affect cycle outcome in a    subset of highly responsive in vitro fertilization patients. Fertil    Steril. 1998 March; 69(3):454-60.

1. A method for improving the implantation and/or pregnancy rate for a female patient undergoing assisted reproduction treatment, which comprises administering one or more daily doses of an aromatase inhibitor (AI) selected from the group consisting of anastrozole, letrozole and vorozole during an assisted reproduction cycle, wherein the doses of AI are selected from amounts effective to reduce serum estradiol levels, wherein the AI is administered starting on any one of days 1 to 5 of a menstrual cycle, and wherein the assisted reproduction treatment is selected from the group consisting of in vitro fertilization (IVF), Gamete Intrafallopian Transfer Procedure (GIFT), Zygote Intrafallopian Transfer Procedure (ZIFT), Intracytoplasmic Sperm Injection (ICSI), Intrauterine Insemination (IUI), and Therapeutic Donor Insemination (TDI).
 2. The method of claim 1, wherein the aromatase inhibitor is administered in a regimen using FSH or a mixture of FSH and LH.
 3. The method of claim 1, wherein the aromatase inhibitor is administered with a plurality of daily doses of FSH or a mixture of FSH and LH.
 4. The method of claim 1, wherein the aromatase inhibitor is administered in 1 to 10 daily doses.
 5. The method of claim 1, wherein the aromatase inhibitor is administered on each of days 3 to 7 of the menstrual cycle.
 6. The method of claim 1, wherein the aromatase inhibitor is administered on each of days 5 to 9 of the menstrual cycle.
 7. The method of claim 1, wherein the aromatase inhibitor is administered in a daily dose of from about 1 mg to about 10 mg.
 8. The method of claim 1, wherein the aromatase inhibitor is letrozole and is administered in a daily dose of from about 2.5 mg to about 10 mg.
 9. The method of claim 1, wherein the aromatase inhibitor is anastrozole and is administered in a daily dose of from about 1 mg to about 4 mg.
 10. The method of claim 1, wherein the aromatase inhibitor is vorazole and is administered in a daily dose of from about 2 mg to about 8 mg.
 11. The method of claim 1, wherein the aromatase inhibitor is administered as a single dose selected from amounts in the range of from about 5 mg to about 500 mg.
 12. The method of claim 1, wherein the aromatase inhibitor is administered as a single dose selected from amounts in the range of from about 10 mg, 20 mg, 25 mg or 30 mg to about 500 mg.
 13. The method of claim 1, wherein the aromatase inhibitor is administered at an amount that lowers estradiol levels to post-menopausal levels in a female.
 14. The method of claim 1, wherein the aromatase inhibitor is administered at an amount that lowers estradiol levels to about 100 pmol/L or less.
 15. The method of claim 1, wherein the aromatase inhibitor is administered at an amount that lowers estradiol levels to about normal physiologic pre-implantation levels in a female.
 16. The method of claim 1, wherein the aromatase inhibitor is administered at an amount that lowers estradiol levels to less than or equal to about 10,000 pmol/L.
 17. The method of claim 1, wherein the aromatase inhibitor is administered at an amount that lowers estradiol levels to within the range of from about 300 pmol/L to about 5000 pmol/L.
 18. The method of claim 1, wherein the aromatase inhibitor is administered orally.
 19. The method of claim 2, wherein FSH or a mixture of FSH and LH is used in a daily dose ranging from about 25 I.U. FSH to about 600 I.U. FSH.
 20. The method of claim 2, wherein FSH or a mixture of FSH and LH is used in a daily dose ranging from about 50 I.U. FSH to about 225 I.U. FSH.
 21. The method of claim 2, wherein FSH or a mixture of FSH and LH is used in a daily dose ranging from about 50 I.U. FSH to about 150 I.U. FSH.
 22. The method of claim 2, wherein the aromatase inhibitor and FSH or mixture of FSH and LH are administered simultaneously, separately or sequentially.
 23. The method of claim 1, wherein the patient is selected from the group consisting of patients who are of reproductive age; who are poor responders to FSH; who do not ovulate with clomiphene citrate; who would show an endometrial thickness of less than 5 mm after a cycle of clomiphene citrate; who suffer from unexplained infertility; who suffer from polycystic ovary syndrome (PCOS); who suffer from endometriosis; who suffer from cervical mucus abnormalities; who suffer from increased baseline FSH concentration; who suffer from elevated FSH concentration; who suffer from male factor infertility; and older patients.
 24. The method of claim 1, wherein a GnRH agonist is administered to the patient.
 25. The method of claim 1, wherein a GnRH antagonist is administered to the patient. 